Homology-sensing mechanisms are critical to meiosis. How homology-sensing is used by chromosomes to find their pairing partners is still a mystery. Yet, genome integrity and the faithful transmission of the genetic information contained in chromosomes depend on these mechanisms. Chromosome pairing is an important and conserved mechanical event. Our working hypothesis is that this mechanical pairing is, in addition, an active "sensing" mechanism used by all meiotic chromosomes to examine their homologues from stem to stern in each meiosis. In this process, chromosomes use the sophisticated meiotic trans-sensing machinery to evaluate their pairing partners. Failure of "sensing" or "pairing" of a discrete DNA region because of the presence of a heterologous region, or the presence of a deletion on the opposite chromosome (i.e., the lack of a homologous region), triggers meiotic silencing-a novel meiotic RNA silencing mechanism. Once activated, the meiotic silencing machinery produces a diffusible silencing signal specific to the unpaired DNA. This signal then, silences the expression of all genes homologous to the ones contained in the unpaired region, whether they are paired or unpaired. The objective of this research is to identify all the players that participate in, and to dissect the molecular mechanisms used by meiotic trans-sensing and meiotic silencing in Neurospora. During this funding period we will develop a series of interrelated projects aimed at defining how homologs "sense" each other and at characterizing mutants affected in these processes. Understanding chromosome sensing is important, for it will lead us to a better understanding of the surveillance mechanisms used by cells to detect "foreign" sequences and how these surveillance mechanisms work to inactivate them, knowledge that has great potential for the therapeutic manipulation of gene expression in all organisms. Understanding these mechanisms can aid our understanding of similar mechanisms in humans, where they participate in both development and disease.